The present invention concerns Diels-Alder reactions of epoxybutene and derivatives thereof, and compounds produced from such reactions.
U.S. Pat. No. 2,616,899 to Ladd reports the Diels-Alder reaction of hexachlorocyclopentadiene with epoxybutene (EpB). The Diels-Alder product was found to be a flame retardant and a stabilizer for polyvinyl chloride (PVC).
In 1989, a Kodak Research Laboratories technical report described the screening of various dienes in Diels-Alder reactions with EpB. Most reactions, including that with cyclopentadiene, produced none of the desired cycloaddition adduct. Only EpB reacted with diphenylisobenzofuran to produce a Diels-Alder cycloadduct, at 38% yield.
Cyclic compounds are useful for a variety of purposes, including the production of polymers and copolymers as described in U.S. Pat. No. 3,277,036 to Whitworth and Zutty and U.S. Pat. No. and 3,494,897 to Reding et al. Accordingly, there is a need for new ways to carry out, the Diels-Alder reaction, and a need for products thereof.
The Diels Alder reaction of certain dienes with certain dienophiles, when carried out under pressure, can be utilized to produce cyclic and bicyclic compounds described herein.
Accordingly, a first aspect of the present invention is a method of making a bicyclic compound selected from the group consisting of compounds of Formula X and compounds of Formula XI: 
wherein:
R, R1, R2, R3, and R4 are each independently selected from the group consisting of H, and C1-C4 lower alkyl; and
R11 and R12 each independently represent xe2x80x94H, xe2x80x94OH, xe2x80x94OCOCH3, xe2x80x94OCH2C6H5, or xe2x80x94OR13 wherein R13 represents C1-C4 lower alkyl, or
R11 and R12 together represent xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(CH3)2xe2x80x94Oxe2x80x94; comprising reacting a diene according to Formula I: 
wherein R, R1, R2, R3, and R4 are as given above with a dieneophile according to Formula VI: 
wherein R11 and R12 are as given above in a Diels-Alder reaction at a pressure greater than atmospheric pressure to yield a compound selected from the group consisting of compounds of Formula X and compounds of Formula XI.
A second aspect of the invention is a method of making a bicyclic compound selected from the group consisting of compounds of Formula XII and Formula XIII: 
wherein:
R, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of H, and C1-C4 lower alkyl; and
R11 and R12 each independently represent xe2x80x94H, xe2x80x94OH, xe2x80x94OCOCH3, xe2x80x94OCH2C6H5, or xe2x80x94OR13 wherein R13 represents C1-C4 lower alkyl, or
R11 and R12 together represent xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(CH3)2xe2x80x94Oxe2x80x94; comprising reacting a diene according to Formula II: 
wherein R, R1, R2, R3, R4 and R5 are as given above with a dieneophile according to Formula VI: 
wherein R11 and R12 are as given above in a Diels-Alder reaction at a pressure greater than atmospheric pressure to yield a compound selected from the group consisting of compounds of Formula XII and compounds of Formula XIII.
A third aspect of the present invention is a method of making a compound selected from the group consisting of compounds of Formula XIV and Formula XV: 
wherein:
R6 is xe2x80x94H;
R7 is xe2x80x94H or xe2x80x94CH3; and
R11 and R12 each independently represent xe2x80x94H, xe2x80x94OH, xe2x80x94OCOCH3, xe2x80x94OCH2C6H5, or xe2x80x94OR13 wherein R13 represents C1-C4 lower alkyl, or
R11 and R12 together represent xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(CH3)2xe2x80x94Oxe2x80x94; comprising reacting a diene of Formula III or Formula IV: 
with a dieneophile according to Formula VI: 
wherein R11 and R12 are as given above in a Diels-Alder reaction at a pressure greater than atmospheric pressure to yield a compound selected from the group consisting of compounds of Formula XII and compounds of Formula XIII.
A further aspect of the present invention is a method of making a bicyclic compound selected from the group consisting of compounds of Formula XVI and compounds of Formula XVII: 
wherein R, R1, R2, R3, R4, R13, R14, R15 and R16 are each independently selected from the group consisting of H, and C1-C4 lower alkyl; comprising
reacting a diene according to Formula I: 
wherein R, R1, R2, R3, and R4 are as given above with a dieneophile according to Formula VII: 
wherein R13, R14, R15 and R16 are as given above in a Diels-Alder reaction at a pressure greater than atmospheric pressure to yield a compound selected from the group consisting of compounds of Formula XVI and compounds of Formula XVII.
A still further aspect of the present invention is a method of making a bicyclic compound selected from the group consisting of compounds of Formula XVII and compounds of Formula XIX: 
wherein R, R1, R2, R3, R4, R5, R13, R14, R15 and R16 are each independently selected from the group consisting of H, and C1-C4 lower alkyl; comprising reacting a diene according to Formula II: 
wherein R, R1, R2, R3, R4 and R5 are as given above with a dieneophile according to Formula VII: 
wherein R13, R14, R15 and R16 are as given above in a Diels-Alder reaction at a pressure greater than atmospheric pressure to yield a compound selected from the group consisting of compounds of Formula XVIII and compounds of Formula XIX.
A still further aspect of the invention is a method of making a compound according to Formula XX 
wherein R6 is xe2x80x94H, R7 is xe2x80x94H or xe2x80x94CH3, and R13, R14, R15 and R16 are each independently selected from the group consisting of H and C1-C4 alkyl;
comprising reacting a diene of Formula III or Formula IV: 
with a dieneophile according to Formula VI: 
wherein R13, R14, R15 and R16 are as given above in a Diels-Alder reaction at a pressure greater than atmospheric pressure to yield a compound of Formula XX.
The present invention also provides compounds, particularly novel compounds, produced by the methods described above.
The present invention concerns the reaction of certain dienes as described below with epoxybutene or epoxybutene derivatives as a dienophile, as also described below, to form cyclic product compounds as described below.
A. Dienes.
Dienes that may be used to carry out the present invention include isoprene, butadiene, cyclohexadiene, cyclopentadiene, and derivatives thereof.
Cyclopentadiene, cyclohexadiene and derivatives thereof that may be used to carry out the present invention are illustrated by Formulas I and II below: 
R, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of H, and C1-C4 lower alkyl.
Isoprene and butadiene, which may also be used as dienes to carry out the present invention, are illustrated by Formulas III and IV below: 
B. Dienophiles.
The present invention may be carried out with epoxybutene (EpB) as the dienophile, which has the structure according to Formula V below, or EpB and derivatives thereof which are generally represented by Formula VI below: 
R11 and R12 in Formula VI, may together represent xe2x80x94Oxe2x80x94, in which case Formula VI represents epoxybutene as shown in Formula V. R11 and R12 may also represent xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(CH3)2xe2x80x94Oxe2x80x94, each of which forms a five member ring system. Such compounds are epoxybutene derivatives.
In addition, R11 and R12 may each independently represent xe2x80x94H, xe2x80x94OH, xe2x80x94OAc (xe2x80x94OCOCH3), xe2x80x94OBz (xe2x80x94OCH2C6H5), or xe2x80x94OR13 wherein R13 represents C1-C4 lower alkyl, preferably methyl. In particular preferred embodiments of formula VI above,
R11 is xe2x80x94H and R12 is xe2x80x94OH;
R11 is xe2x80x94OAc and R12 is xe2x80x94OAc;
R11 is xe2x80x94OR13 R12 is xe2x80x94OAc;
R11 is xe2x80x94OBz and R12 is xe2x80x94OH; and
R11 is xe2x80x94OH and R12 is xe2x80x94OH.
Still further dienophiles that may be used to carry out the present invention are compounds of Formula VII: 
In which R13, R14, R15 and R16 are each independently selected from the group consisting of H and C1-C4 lower alkyl.
C. Reaction Conditions.
The Diels-Alder reaction may be carried out in any suitable solvent, typically an organic solvent and typically an inert solvent, (e.g., a polar or nonpolar organic solvent), and preferably an aprotic solvent, such as toluene, tetrahydrofuran (THF), etc., or by heating the reactants together without a solvent.
The reaction may be carried out at any suitable temperature, typically in the range of about 65, 100 or 150 to 230, 250, or 300 degrees Celsius or more.
The time of the reaction is not critical, and may be carried out for from about 1 or 2 hours to 10, 20 or 100 hours or more. The reaction may be carried out as a batch reaction or as a continuous reaction.
The reaction may be carried out any suitable pressure, but is preferably carried out at a pressure greater than atmospheric pressure. For example, the reaction may be carried out at a pressure of from at least about 2, 4, 6 or 8 or 10 atmospheres to about 14, 18, 20, 30, 100, 1,000 or even 10,000 atmospheres or more.
If desired, the reaction may be catalyzed by the addition of a Lewis acid or other suitable catalyst, in accordance with known techniques.
Either the diene or the dienophile may be present in the reaction in excess amounts, or approximately equimolar amounts of the two reactants may be used. As is known in the literature, dicyclopentadiene may be used at reaction temperatures sufficiently high (e.g., above about 150 degrees C.) to produce free cyclopentadiene from its dimer.
The reactions described herein can produce either single isomeric products or mixtures of exo/endo isomers, depending on the substrate structures and reaction conditions. Where mixtures of compounds are formed the pure compounds can be isolated from those mixtures in accordance with known techniques.
D. Reaction Products.
A variety of different reaction product compounds may be produced by the reactions described herein, depending upon the choice of diene, dienophile, and reaction conditions.
In general, reaction product compounds of the present invention where the diene in the reaction is cyclopentadiene or a derivative thereof according to Formula I, are compounds of Formula X and Formula XI below. (Note that Formulas herein are intended to cover both the exo and endo forms of the compounds. Stereochemistry is not shown in the compounds, but the present invention is intended to encompass both enantiomerically pure compounds as well as racemic and other mixtures of isomers). 
In Formulas X and XI, R, R1, R2, R3, R4, R11, and R12 are as described above in connection with diene and dienophile reactants. In one embodiment, compounds of Formulas X and XI, are subject to the proviso that, when R1, R2, R3, and R4 are each H, then R11 and R12 are not together xe2x80x94Oxe2x80x94. Alternatively stated, in compounds of Formulas X and XI, when R11 and R12 together represent xe2x80x94Oxe2x80x94, then at least one of R1, R2, R3, and R4 is not H.
Reaction product compounds of the present invention, where the diene in the reaction is cyclohexadiene or a derivative thereof according to Formula II, are compounds of Formula XII and Formula XIII: 
In Formulas XII and XIII, R, R1, R2, R3, R4, R5, R11, and R12 are as described above in connection with diene and dienophile reactants.
Reaction product compounds of the present invention, where the diene in the reaction is isoprene or isobutadiene, are compounds of Formula XIV and Formula XV: 
In Formulas XIV and XV, R11 and R12 are as described above in connection with dienophile reactants. R6 is xe2x80x94H, and R7 is xe2x80x94H or xe2x80x94CH3 (for butadiene or isoprene reactants, respectively).
Reaction product compounds of the present invention, where the dienophile is a compound of Formula VII above and the diene is a compound of Formula I above, include compounds of Formulas XVI and XVII: 
In Formulas XVI and XVII above, R, R1, R2, R3, R4, R13, R14, R15,and R16 are as described above in connection with diene and dienophile reactants.
Reaction product compounds of the present invention, where the dienophile is a compound of Formula VII above and the diene is a compound of Formula II above, include compounds of Formulas XVIII and XIX: 
In Formulas XVIII and XIX above, R, R1, R2, R3, R4, R5, R13, R14, R15 and R16 are as described above in connection with diene and dienophile reactants.
Reaction product compounds of the present invention, where the dienophile is a compound of Formula VII above and the dienes isoprene or butadiene as set forth in Formulas III-IV above, are given in Formula XX: 
In Formula XX, R13, R14, R15 and R16 are as described above in connection with the dienophile reactant. R6 is H, and R7 is xe2x80x94H or xe2x80x94CH3 (for butadiene or isoprene reactants, respectively).
E. Uses.
The reaction product compounds of the present invention are useful as monomers for the preparation of polymers (see, e.g., U.S. Pat. No. 3,494,897; U.S. Pat. No. 3,277,036) may be used as monomers in ring opening metathesis polymerizations (ROMP) to form polymers, and, where the monomers contain an epoxy group, may be used as monomers to form in epoxy polymers, which polymers may in turn be used for a variety of purposes, including but not limited to being formed into useful articles such as sinks, fasteners, and the like in accordance with known techniques. In addition, the compounds are useful as polymer additives for modifying the properties of polymers, as intermediates for the manufacture of physiologically active and pharmaceutically active compounds, including pesticides, fungicides, insecticides, etc., and are useful per se as pesticides, fungicides, and insecticides.
Particular reactions that may be used to carry out the present invention, and products thereof, are set forth in the following sections.
F. The Thermal Diels Alder Reactions of Epoxybutene and Derivatives Thereof with Cyclopentadiene.
Epoxybutene and its derivatives undergo the thermal Diels Alder reaction with selected dienes under appropriate conditions. For example, cyclopentadiene reacts with epoxybutene at 170xc2x0 C. in a sealed tube to yield the expected cycloadducts in a endo to exo ratio of about 76:24 (Scheme 1). 
The reaction proceeds with the formation of more cycloadduct products when a large excess of dienophile and longer reaction times are used. The formation of dicyclopentadiene is prominent when using epoxybutene as the dienophile. This is possibly a result of the low reactivity of the dienophile. This problem can be overcome with the use of longer-reaction times.
Cyclopentadiene reacts with 2,5 dihydrofuran under similar conditions as those of epoxybutene to form the expected cycloadducts (Scheme 2). 
2,5 dihydrofuran is an ideal substrate for the study of these [4+2] cycloadditions because it doesn""t have a preexisting chiral center. Therefore, we believe that the product shown in Scheme 2 is a good model for the NMR assignment of the endo and exo diastereomers.
From Diagram 1, we noticed that the symmetry of the molecules allows us to unambigously assign the protons by region. We also notice that the differences in the exo and the endo structure are quite evident. The spectrum shows that the exo bridge protons (H3 and H4) are effected by the oxygen atom of the furan ring. The proton nearest the oxygen (H4) is deshielded the most in comparison to it""s endo isomer analog and the protons above the alkene (H3, H3xe2x80x2) are shielded by the alkene anisotropy.
Cyclopentadiene also reacts with 3,4-diacetoxy-2-butene (Scheme 3). We have not yet determined the diastereomeric ratio for this mixture due to the inability to separate the diastereomers via GC. Nevertheless, we suspect the presence of both the endo and exo diastereomers as the product. 
The reaction in Scheme 4 proceeded with a 95:5 ratio of endo to exo. Just as in the 2,5 dihydrofuran case, the lack of a preexisting chiral center insures the formation of only one set of possible diastereomeric products. 
The reaction in Scheme 5 below proceeded with about a 1:1 ratio of endo to exo products. It is also noteworthy to observe the yield and reaction conditions of the 4-ethenyl-1,3 dioxolan-2-one. Milder heating and less reaction time produced 84% yield of cycloadducts. 4-Ethenyl-1,3 dioxolan-2-one is a better dienophile than the other dienophiles tested to date. 
2,2-Dimethyl-4-Ethenyl-1,3-Dioxolane 
G. Other Thermal Diels-Alder Reactions.
Reactions with Cyclohexadiene: 
These compounds have been observed by 1H NMR and GC/MS. 
These isoprene reactions were maintained with a great excess of isoprene to dienophile. Under these conditions, we have noted that isoprene has a tendency to polymerize. Using hydroquinone only helped to catalyze the polymerization (possibly by H+ catalysis). Other radical scavengers may work better than hydroquinone. We also noted that even under longer reaction times, the yields were not as high as those that were observed in the cyclopentadiene case.
The present invention is explained in greater detail in the following non-limiting Examples.